Project Summary The rapid formation of new memories and the recall of old memories to inform decisions is essential for human cognition, but the underlying neural mechanisms remain poorly understood. The long-term goal of this research is a circuit-level understanding of human memory to enable the development of new treatments for the devastating effects of memory disorders. Our experiments utilize the rare opportunity to record in-vivo from human single neurons simultaneously in multiple brain areas in patients undergoing treatment for drug resistant epilepsy. The overall objective is to assemble a multi-institutional (Cedars-Sinai/Caltech, Johns Hopkins, U Toronto, Children?s/Harvard), integrated, and multi-disciplinary team. Jointly, we have the expertise and patient volume to test key predictions on the neural substrate of human memory. We will utilize a combination of (i) in- vivo recordings in awake behaving humans assessing memory strength through confidence ratings, (ii) focal electrical stimulation to test causality, and (iii) computational analysis and modeling. We will apply these techniques to investigate three overarching hypothesis on the mechanisms of episodic memory. First, we will test the prediction that stimulus-specific persistent activity is essential for memory formation (Aim 1). Second, we will determine whether neurons accumulate memory-derived evidence to inform retrieval decisions and/or the confidence (a type of metacognition) about retrieval decisions (Aim 2). Third, we will test the hypothesis that visually-and memory selective cells emerge gradually during temporally extended episodes of experience to gradually create and solidify memories (Aim 3). The expected outcomes of this research are an unprecedented characterization of how declarative memories are formed and used in the human brain. This work is significant because we move beyond a ?parts list? of neurons and brain areas by testing circuit-based hypothesis by simultaneously recording single-neurons from multiple frontal cortical and subcortical temporal lobe areas in humans who are forming, declaring and describing their memories. The proposed work is unusually innovative because we combine single-neuron recordings in multiple areas in behaving humans, develop new methods for non-invasive localization of implanted electrodes and electrical stimulation and directly test long-standing theoretical predictions on the role of evidence accumulation in memory retrieval. A second significant innovation is our team, which combines the patient volume and expertise of several major centers to maximally utilize the rare neurosurgical opportunities available to directly study the human nervous system. This innovative approach permits us to investigate circuit-level mechanisms of human memory that cannot be studied non-invasively in humans nor in animal models due to their unclear relevance to human memory and its diseases. This integrated multi-disciplinary combination of human in-vivo single-neuron physiology, behavior, and modeling will contribute significantly to our understanding of the circuits and patterns of neural activity that give rise to human memory, which is a central goal of human neuroscience in general and the BRAIN initiative in particular.